Current Opinion in Chemical Biology最新文献

Within their native milieu of the cell, the activities of enzymes are controlled by a range of factors including protein interactions and post-translational modifications. The involvement of these factors in fundamental cell biology and the etiology of diseases is stimulating interest in monitoring enzyme activities within tissues. The creation of synthetic substrates, and their use with different imaging modalities, to detect and quantify enzyme activities has great potential to propel these areas of research. Here we describe the latest developments relating to the creation of substrates for imaging and quantifying the activities of glycoside hydrolases, focusing on mammalian systems. The limitations of current tools and the difficulties within the field are summarised, as are prospects for overcoming these challenges.

Current standard-of-care for metastatic colorectal cancer patients includes chemotherapy and anti-angiogenic or anti-epidermal growth factor receptor for microsatellite stable tumors and pembrolizumab for microsatellite instable tumors. However, despite the available therapies, the prognosis remains poor. In recent years, new drugs combined with immune checkpoint inhibitors have been tested in microsatellite stable metastatic colorectal cancer patients, but the benefit was modest. Here, we review the metabolic interactions between the immune microenvironment and cancer cells. More specifically, we highlight potential correlatives of tumor immune and metabolic features with transcriptomic classifications such as the Consensus Molecular Subtype. Finally, we discuss the unmet need of immune-metabolic signatures and the value of a new signature (IMMETCOLS) for guiding new strategies in metastatic colorectal cancer. We conclude that the field is ready to propose customized strategies for modifying metabolism and improving immunotherapy and targeted therapy efficacy.

Metabolomics has rapidly been adopted as one of the key methods in nutrition research. This review focuses on the recent developments and updates in the field, including the analytical methodologies that encompass improved instrument sensitivity, sampling techniques and data integration (multiomics). Metabolomics has advanced the discovery and validation of dietary biomarkers and their implementation in health research. Metabolomics has come to play an important role in the understanding of the role of small molecules resulting from the diet–microbiota interactions when gut microbiota research has shifted towards improving the understanding of the activity and functionality of gut microbiota rather than composition alone. Currently, metabolomics plays an emerging role in precision nutrition and the recent developments therein are discussed.

PARPs encompass a small yet pervasive group of 17 enzymes that catalyze a post-translational modification known as ADP-ribosylation. PARP1, the founding member, has received considerable focus; however, in recent years, the spotlight has shifted to other members within the PARP family. In this opinion piece, we first discuss surprising findings that some FDA-approved PARP1 inhibitors activate innate immune signaling in cancer cells that harbor mutations in the DNA repair pathway. We then discuss hot-off-the-press genetic and pharmacological studies that reveal roles for PARP7, PARP11, and PARP14 in immune signaling in both tumor cells and tumor-associated immune cells. We conclude with thoughts on tuning PARP1-inhibitor-mediated innate immune activation and explore the unrealized potential for small molecule modulators of other PARP family members as next-generation immuno-oncology drugs.

Due to its nucleophilicity, the thiol group of cysteine is chemically very versatile. Hence, cysteine often has important functions in a protein, be it as the active site or, in extracellular proteins, as part of a structural disulfide. Within the cytosol, cysteines are typically reduced. But the nucleophilicity of its thiol group makes it also particularly prone to post-translational oxidative modifications. These modifications often lead to an alteration of the function of the affected protein and are reversible in vivo, e.g. by the thioredoxin and glutaredoxin system. The in vivo-reversible nature of these modifications and their genesis in the presence of localized high oxidant levels led to the paradigm of thiol-based redox regulation, the adaptation, and modulation of the cellular metabolism in response to oxidative stimuli by thiol oxidation in regulative proteins. Consequently, the proteomic study of these oxidative posttranslational modifications of cysteine plays an indispensable role in redox biology.

DnaK is a chaperone that aids in nascent protein folding and the maintenance of proteome stability across bacteria. Due to the importance of DnaK in cellular proteostasis, there have been efforts to generate molecules that modulate its function. In nature, both protein substrates and antimicrobial peptides interact with DnaK. However, many of these ligands interact with other cellular machinery as well. Recent work has sought to modify these peptide scaffolds to create DnaK-selective and species-specific probes. Others have reported protein domain mimics of interaction partners to disrupt cellular DnaK function and high-throughput screening approaches to discover clinically-relevant peptidomimetics that inhibit DnaK. The described work provides a foundation for the design of new assays and molecules to regulate DnaK activity.

The long luminescence lifetimes and sharp emission bands of luminescent lanthanide complexes have long been recognized as invaluable strengths for sensing and imaging in complex aqueous biological or environmental media. Herein we discuss the recent developments of these probes for sensing metal ions and, increasingly, anions. Underappreciated in the field, buffers and metal hydrolysis influence the response of many responsive lanthanide probes. The inherent complexities arising from these interactions are further discussed.

Chemical elements, especially metals, play very specific roles in the life sciences. The implementation of correlative imaging methods, of elements on the one hand and of molecules or biological structures on the other hand, is the subject of recent developments. The most commonly used spectro-imaging techniques for metals are synchrotron-induced X-ray fluorescence, mass spectrometry and fluorescence imaging of metal molecular sensors. These imaging methods can be correlated with a wide variety of other analytical techniques used for structural imaging (e.g., electron microscopy), small molecule imaging (e.g., molecular mass spectrometry) or protein imaging (e.g., fluorescence microscopy). The resulting correlative imaging is developed at different scales, from biological tissue to the subcellular level. The fields of application are varied, with some major research topics, the role of metals in the aetiology of neurodegenerative diseases and the use of metals for medical imaging or cancer treatment.

Zn²⁺ is involved in various physiological and pathological processes in living systems. Monitoring the dynamic spatiotemporal changes of Zn²⁺ levels in organelles, cells, and in vivo is of great importance for the investigation of the physiological and pathological functions of Zn²⁺. However, this task is quite challenging since Zn²⁺ in living systems is present at low concentrations and undergoes rapid dynamic changes. In this review, we summarize the design and application of fluorescent probes for Zn²⁺ imaging in organelles, cells, and live organisms reported over the past two years. We aim to provide inspiration for the design of novel Zn²⁺ probes for multi-level monitoring and deepen the understanding of Zn²⁺ biology.